The objective of the proposed project is to study postsynaptic mechanisms at the vertebrate motor end-plate during transmitter action and during prolonged exposure to pharmacologically active agents. Of particular concern will be the action of calcium on the time course of the end-plate conductance change during transmission and during the desensitization of end-plate receptors which occurs with sustained carbamylcholine application. At present there is no direct evidence which reveals the nature of the molecular changes which are presumed to occur during the activation and desensitization of the end-plate membrane receptors. Consequently, these processes must be studied using determinations of the time course of the postjunctional membrane potential and conductance as a useful measure of the molecular events occurring at the membrane receptor sites. It is hoped that the results obtained in this study will increase our general knowledge of the conductance system of the postsynaptic membrane at the motor end-plate and also reveal basic information about the cholinergic receptor site. In particular the proposed project will address itself to the following problems: a. The site of calcium action in accelerating end-plate desensitization. b. The influence of metabolic inhibitors on the activation-desensitization process. c. The time course of recovery from desensitization induced by carbamylcholine. d. A voltage clamp analysis of end-plate desensitization by carbamylcholine. e. The possible role of calcium in determining the time course of end-plate conductance change during transmission.